JPH01500034A - Vaccines and implants - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Vaccines and implants The present invention provides a long-acting implant. ) Regarding the manufacturing method and veterinary vaccines, especially veterinary contraceptive vaccines. It is something that

A large number of pharmaceutical and vaccine compositions for medical and veterinary use are already known. these The compositions generally consist of the active ingredient in admixture with excipients. Active ingredient is in auxiliary agent can be distributed to Auxiliary agents stimulate the animal's immune system and maximize the effectiveness of the active ingredients. It's easy to get things done. However, compositions containing auxiliary agents and active ingredients , the volume of the unit dosage is large. In the case of veterinary drugs, such large ie animals that require animal capture for dose administration? Capture and unit dose of whole drug It is administered to the animal by injection or otherwise, and then the animal is released. like this This method of administration is time-consuming and expensive. Especially in the case of wild animals, such The method of administration is virtually impractical. In addition, in the case of drug administration, vaccines To avoid quality deterioration, refrigeration equipment is generally required.

If a method of administration using substantially small volumes of drug or vaccine compositions is developed; This would be a major contribution to the industry.

vaccine? Place it in a bullet, load it into an air gun, and shoot it at a wild animal. A method of administration has previously been developed that consists of administering the vaccine to wild animals. child ↓A bullet for an air gun can be prepared to a sufficiently small size and is used for this purpose. The active ingredient can be made lyophilic and prepared in the form of a product. However, lyophilic This method of administration cannot be used in the case of vaccines or medicines where administration is not possible. Especially now One of the important things is administering long-lasting contraceptive vaccines to wild animals. The goal is to develop a method to do so.

The main object of the invention is therefore to overcome or eliminate one or more of the disadvantages of the prior art as mentioned above. The goal is to improve it, at least in part.

The present invention (al　biodegradable one-piece material, (1)) Multiple biodegradable microcapsules embedded therein, and (C) Nine effective amounts of the physiologically active ingredient encapsulated in the microcapsules listed below. ? This invention relates to a long-acting implant characterized by containing.

The implants of the present invention are capable of releasing all physiologically active ingredients with a controlled release rate. It is. This physiologically active ingredient is a medicinal and/° or veterinary active ingredient. obtain. This specific implant is a 6D medical or veterinary implant. physiological activity This long-acting implant is particularly advantageous when the vaccine is a vaccine. because, This is because the vaccine can be pre-programmed and administered by the fc1 step method. be. Additionally, this long-acting implant is stable for long periods of time without the need for refrigeration. The biodegradable polymeric material described above may be of any suitable form. this life Degradable polymeric materials can be manufactured into bullet shapes. This biodegradable polymer material is made from bullet shells. It can be prepared in a form that can be inserted into the body. This biodegradable polymer material is It can be prepared in the shape of a rounded bullet for loading into air guns, etc. This biodegradable monomer material is Can be prepared in the shape of a round head. This polymeric material is suitable for small caliber bullets, e.g. It can be adjusted to the shape of a bullet head for a 20-diameter rifle, etc. multiple biodegradable microphones Preferably, microcapsules are used, and multiple microcapsules with multiple degradation ratios are used. Cells (i.e., multiple microcapsules with different rates of degradation) are even more preferred. Delicious. Additionally, the degradation rate of biodegradable polymeric materials is significantly lower than that of biodegradable microcapsules. It is preferable that the decomposition rate L#) is high.

The biodegradable polymeric material can be prepared from any suitable biodegradable monomeric material.

Polymers can be used that act as auxiliaries for veterinary active ingredients. water soluble polymer can be used. This polymeric material is released approximately 8-24 hours after entering the animal's body. Preferably, it is something that decomposes. For example, polyvinylpyrrolidone polymers can be used. A polyvinylpyrrolidone polymer copolymer can be used. place Sufficiently withstand the impact of certain administration methods (e.g., using a gun). A polymer should be selected that has the desired impact strength. If necessary, An impact resistant coating can be applied to the outer surface of the degradable polymeric material. Other standard formulations Components can also be incorporated into the polymer matrix. Examples of such ingredients include fillers. I can give you a working agent.

Furthermore, it is also possible to mix other active ingredients (all polymers) with IJ Lux.

Antibiotics, supplementary foods, drugs, etc. can also be added.

The biodegradable polymeric material can be prepared by any suitable method. For example, this Biodegradable polymeric materials can be manufactured using injection molding techniques.

As mentioned above, the sustained-release implant of the present invention comprises: (b) embedded in a polymeric material; Multiple biodegradable microcapsules Contains.

The plurality of biodegradable microcapsules mentioned above are added to the polymeric material during the performance of the polymerization process. can. Alternatively, biodegradable microcapsules can be added during the molding process. is also possible. For example, tabletting techniques are used to press biodegradable polymeric materials into the desired shape. Can be made into compressed tablets. A tablet press can be used for this purpose. Before performing the molding operation Microcapsules and polymers can be mixed.

The biodegradable microcapsules can be made from any suitable biodegradable polymeric material. Ru. Polyester polymers can be used. Polymerization of hydroxy acids and their derivatives A body-molded copolymer is preferred.

Preferred biodegradable microcapsules are relatively low molecular weight, glycolic acid, milk Acids, their derivatives, polymers or copolymers of mixtures (first polymer), and Relatively high molecular weight polymers of glycolic acid, lactic acid, their derivatives or mixtures. is a microcapsule made from a copolymer (second polymer). the plurality of said More preferably, the biodegradable microcapsules are made to have a seed particle size.

A plurality of biodegradable microcapsules used in preferred embodiments of the invention are compared to low decomposition (dlilgraCLatiOn) rate, medium decomposition rate, The capsule contains microcapsules or mixtures thereof with a relatively high decomposition rate. It is. As already mentioned, changing the decomposition rate and changing the color will reduce the amount of contamination and physiologically active components. The rate of release in minutes can be determined by changing the composition of the polymer, modifying/or modifying the molecules of the polymer used. It can be modified in various ways by changing the amount. In a preferred embodiment, a veterinary contraceptive When using the above-mentioned administration device for administration of lactin, it may be necessary to use it for a short period of several days. Any decomposition rate between 1 year and 1 year can be selected. For example, tJl - 12 weeks A medium decomposition rate can be selected. Also, over a long period of about 2 to 6 years, A lower decomposition rate can be selected. For example, during a period of 6 years or less, Contraceptive tX can be released at a controlled rate for full duration of effect.

The rate of decomposition of biodegradable microcapsules also varies depending on their particle size.

It is preferable to use biodegradable microcapsules of at least two or more particle sizes together. Yes. By using two or more types of substances with different molecular weights, physiologically active ingredients can be obtained. Formulations can be produced that can release more than one fraction of the amount at four or more release rates.

Preferred embodiments of the present invention provide the following production method, namely, the biodegradable A biodegradable polyester of a given molecular weight used for the preparation of biocompatible microcapsules. (a) Glycolic acid, milk Polymerization reaction of one or more monomers consisting of acids, derivatives and mixtures thereof and a predetermined amount metal catalyst and all prepared, (1)) Polymerizing the above-mentioned one or more monomers at high temperature in the presence of the above-mentioned catalyst. Ru A manufacturing method is provided.

Monomer of 1m or more selected from glycolic acid, lactic acid, derivatives and mixtures thereof is a cyclic diester, 1,4-dioxane-2,5-dione and 6,6-dione. Nine selected from chiru-1,4-dioxane-2,5-dione. is preferable.

The molecular weight of the polyester produced can be controlled by adjusting the amount of metal catalyst added. Ru.

Chemistry of polyester production Polyesters of α-hydroxycarboxylic acids are suitable for ring-opening polymerization reactions of cyclic diesters. ↓It can be manufactured. The ninth example is glycolic acid polyester (1), which is 1,4-dio It can be produced by polymerization of xane-2,5-dione (IV).

(IV) (1) This type of polymerization reaction is classified as an addition polymerization reaction. because, This is because there is no separation of small molecules during this reaction process. This reaction (IV) proceeds with successive additions of (IV), increasing the chain length of the polymer.

This cyclic compound polymerizes due to its ionic structure, and the reaction is catalyzed by polyvalent metal salts. Proceed below.

Examples of metal catalysts that can be used in the above process include zinc salts such as zinc oxide and zinc carbonate; Organic tin salts such as stannous octanoate, stannous octoate, processed aluminum salts of barium, barium, magnesium or titanium. Type of catalyst used The quantity used determines the polymerization reaction rate, i.e. the amount produced within a given reaction time. Determine the average molecular weight of the polymer.

The length of the polymer chains can also be controlled through the use of chain growth regulators. water, not yet Compounds such as α-hydroxycarboxylic acids in the reaction are prot onatθ), is added to the terminal unit of the polyester chain to stop this polymerization reaction. let

Preparation and properties of dimers As mentioned above, α-hydroxycarboxylic acids can be activated in the form of cyclic dimers. catalyst When heated in the presence of , it polymerizes into polyester. 1.4-Geo Xane-2,5-dione (IV) and 6,6-dimethyl-1,4-dioxane -2,5-dione (V) is a ring of glycolic acid (I) and lactic acid (II), respectively. It is a dimer. These two compounds are each referred to as “glycolide” in the literature. and is often referred to as "lactide."

1,4-Dioxane-2,5-dione (IV) can be produced by several methods. For example, it can be produced by thermal decomposition of sodium chloroacetate (Production method 1). this The most convenient and economical method for preparing various dioxa/diones is to The quantification reaction is carried out under conditions that allow continuous desorption of water. many other officials As with functional molecules, α-hydroxycarboxylic acids are highly susceptible to intramolecular cyclization. There is a q direction that is easy to occur, and the intermolecular condensation reaction will be suppressed. Polymerization reaction The factor that determines which dimerization reaction occurs is the reaction conditions. , especially temperature.

As shown in Production Method 1, lactic acid dimer can be easily produced by this method. . This reaction can be carried out at temperatures as high as 100°C and below the boiling point of the product. Ru. Continuously remove water from the reaction mixture to direct the reaction toward total ester production . Thereafter, vacuum is applied prior to distillation of the nine-dashi dione product.

In fact, glycolic acid (I) t- is first polymerized to produce a low molecular weight polyester. After that, this polyester is subjected to a depolymerization reaction to produce dione (IV) t- This is then distilled off from the reaction mixture (Production method 1).

When carrying out the direct polymerization of hydroxy acids, as in the first step, K is added to the reaction mixture ( It is difficult to completely remove water from the so-called reaction melt. Therefore, this By applying the direct condensation polymerization method of It is generally not possible to precipitate the lyester. For this reason, cyclic die A preferred production method is to carry out addition polymerization using stell.

heating HOCH2C02H-〉-(OCH2CO2CH2CO)x-・H2O(I) Production of copolymers of glycolic acid and lactic acid and copolymerization of glycolic acid and lactic acid The combination involves 1.4” oxane-2,5-dione (IT) and 6.6-cymethyl- 1. Performing the polymerization operation using a mixture of 4-dioxane-2,5-dione (V) It can be manufactured by The mixing ratio of each dione can be varied.

In this method, a catalyst is added to a melt of a cyclic diester and the reaction mixture is heated to a high temperature for an extended period of time. Heat for an hour. As previously mentioned, a variety of catalysts can be used. The preferred catalyst is tetra phenyltin, stannous octoate and stannous octanoate. First tin o Kutoate (■) is also called stannous 2-ethylhexanoate, This is a tin salt of branched 08 carvone. Stannous octanoate (1!:) is It is a tin salt of a linear C8 carboxylic acid.

(■) (■) This polymer was dissolved in chloroform, the insoluble unreacted diester was filtered off, and the filtrate was This polymer can be purified by placing it in methanol. occurs at this stage The polyester precipitate can be recovered by filtration and vacuum drying operations.

As already mentioned, the specific implant of the present invention further comprises biodegradable microcapsules. It contains an effective amount of the physiologically active ingredient in t-form encapsulated in cells. This physiological activity The ingredients may be of any type. This ingredient is a medical friend and is used as a vaccine. good. Vaccines are preferred.

Examples of vaccines include contraceptive vaccines, clostridial vaccines [e.g., C, S , Ltd. (Australia) under the trademark "Five, In, One". vaccines], E. coli vaccines [9, for example, biotechnology, swine E. coli vaccine available from Tralian, a viral protein vaccine, Allergy vaccines are available. Examples of pharmaceuticals that can be used as physiologically active ingredients medicines that require a complete administration program in advance (e.g., roundworm-killing drugs) ) can be given. If a vaccine is used, the active ingredients of this vaccine should be Auxiliary substances commonly required under the conditions may also be administered. biodegradable microphone It is also possible that the rocapsule itself acts as an auxiliary agent. Used in preferred embodiments of the invention The physiologically active ingredient used is a veterinary contraceptive vaccine, which contains an effective amount of A hormone, a fragment thereof, or a derivative thereof, and an effective amount proteins, and their analogues, do not contain hormone-protein combinations, including derivatives. It is something that

In the case of simple hormones and simple protein components, these can be used in complex form. Ru. If there are two or more hormone components, each of them may be the same or mutually exclusive. It can be used in the form of a complex with different protein components.

The sex hormone component of veterinary contraceptive vaccines is the male hormone, a hormone common to both sexes. , female hormones contain a mixture of them. Particularly preferable Examples of hormones common to both sexes include luteinizing hormone-releasing hormone (LH) (this is a plain (brain) 47”, an egg made with luteinizing hormone. Examples include cell maturation hormone (which is a pituitary hormone).

Additionally, male hormones such as testosterone can be used. Nystrodan's When female hormones can also be used.

The sex hormone component is approximately 25-75% by weight (based on the total weight of veterinary contraceptive vaccine). Wear.

The protein components in veterinary contraceptive vaccines may include sex hormones, fragments or derivatives thereof. Protein molecules capable of forming a complex of can be selected from among their analogues. Al the cow Tetanus toxoid proteins of animal origin, such as zymin and gamma globulin proteins. gamma-globulin proteins of human origin, such as white matter, serum albumin, and globulin; Proteins of bacterial origin containing white matter can be used.

The protein or protein analogue weighs approximately 25-75% by weight (the entire veterinary contraceptive vaccine composition). weight basis) can be used. This hormone-protein complex is a protein carrier i o　o　o　o　o　o　o Dalton hit Shihazote/Molecularly better.

In a preferred embodiment, the veterinary contraceptive vaccine is manufactured using the following process. activity Tetanus toxin has nine cross-linked foundations, and multiple thiol foundations in a reduced state The luteinizing hormone-releasing hormone peptide M9 has an analogue thereof, and this It is manufactured by conjugating proteins and peptides.

The activated bridging group in tetanus toxin is preferably a maleimino group. Pepti The thiol group in DomaL's analogues is preferably in a reduced state; This is certainly not a dithiol group. In case a disulfide group is formed, This peptide and its analogs cannot form complexes with proteins.

After the complex is formed, the complex is purified in a purification step. This spirit The manufacturing process may include gel filtration. Polyacrylamide gel can be used .

Once the veterinary contraceptive vaccine has been manufactured, it is then encapsulated in microcapsules. You can enter.

Accordingly, the present invention also provides that glycolic acid, lactic acid, derivatives thereof or L is the biological component of the mixture. A degradable polyester is prepared by preparing a copolyester and a physiologically active ingredient. Physiologically active ingredients are encapsulated in polyester copolyester to create a micro- It also relates to a method for producing microcapsules, which involves making capsules.

Preferably, this capsule forming step is performed in such a way that the polyester copolyester is filled with a copolyester. Mixing with physiologically active ingredients in a suitable solvent: Precipitation of the processed polyester It covers all operations.

For example, if the physiologically active ingredient is a veterinary contraceptive vaccine, protein-protein Lumon complex can be incorporated into mixtures of lactic and glycolic acid polyesters. An easy-to-use technique is available to dissolve polyester and pharmaceuticals in organic solvents, Since it is evaporated to create a casting film, it is possible to create a microphone using a phase separation method. Various techniques are available for various operations up to making capsules. protein mixture The following two techniques are preferred for this purpose.

(1) The protein-hormone complex to be mixed is suspended in a solvent. This solvent Not miscible with reester. −This solvent is modified by adding dioxane. Stir vigorously. This addition causes the polyester to bind the insoluble composite particles to the nuclide. It precipitates in the form of This slurry is then evaporated to form a thin film. , a polymer matrix in which the complex is encapsulated is recovered.

This product can be ground to a powder of suitable particle size or shaped into a desired shape by a molding operation. Can be processed into implants.

(II) The protein-hormone complex to be made into capsules is dissolved in a fine polymer solution. Suspend in liquid. The solvent in this polymer solution completely dissolves the polymer, but the composite does not dissolve. An example of this is chloroform. This solution is completely emulsified. The protein is then evaporated under reduced pressure to precipitate the protein at the periphery of the complex. formed on the spheres, or with a solvent that does not dissolve the polymer (i.e., a nonsolvent). For example, methanol is added to precipitate the polymer and form microcapsules. be.

The total amount of contraceptive vaccine in each implant is determined based on the animal to be treated and the desired avoidance. Various changes can be made depending on the duration of the pregnancy effect. Place for 6-step controlled release implants In some cases, a minimum of 3 mg of active vaccine ingredient can be incorporated into the polymer matrix. Ru.

The present invention also provides -) biodegradable polymeric materials; (b) a plurality of biodegradable microcapsules encapsulated therein, and (C1 an effective amount of a physiologically active ingredient encapsulated in the aforementioned microcapsules) administering at least one sustained-release implant containing the following to humans or animals (including humans); The present invention also relates to a method for treating and treating animals characterized by the following.

Preferred physiologically active ingredients are contraceptive vaccines, clostridial vaccines, colonic vaccines, Fungal vaccines, ora'l protein vaccines, and areA/E vaccines The m vaccine is selected from the following.

In order to illustrate the invention in more detail, the following examples are presented. However, in the example The description is merely illustrative and the scope of the invention is not limited thereto in any way. It should be understood that this is not the case.

Example 1 The following operations were performed according to the method described above. A predetermined amount of glue, L-3, (5-dimethy L-1,4-dioxane-2,5-dione (D,L-lactide) 9. Repeat the recrystallization operation until it shows a certain melting point.

A batch polymerization operation was carried out on a scale of 5-109, the polymer was dissolved in chloroform and the methane The polymer was recovered by pouring it into alcohol.

9 using a ready-made stannous octoate catalyst. p-) Rue/sulfonic acid is 7gma It is supplied by Chemical Company and is in the nonahydrate form. First of all, all this is water. toluene? The sample was dried by azeotropic distillation and then recrystallized from toluene. La Uril alcohol is vacuum distilled before use.

The viscosity of the solution was measured using a U-shaped capillary viscometer. All viscosities are determined by the solvent and The chloroform reaction was carried out using tetrahydrofuran at 60°C.

Four types of polymer samples (batch 1-4) were prepared from D, L-lactide under the following conditions. friend.

(1) Stannous octoate) (0,10 tin, W/W): Seal tightly and react under vacuum. 160: 6 hours.

('2J stannous octo-A) (0,02 section, 1/'W); Closed and under vacuum React for 160 hours for 6 hours.

(3) Stannous octoate) (0.05%, v/W): Catalyst activator Use 1 ko, oi% of lauryl alcohol as a chain control agent: Seal the container and allow the reaction to proceed. Do: Heat to 200℃ for 2.5 hours.

(4) p-r luenesulfonic acid catalyst (1 t, W/W): Seal and conduct the reaction under vacuum. Do: Heat to 120℃ for 5 days.

All these reactions are performed under high vacuum. Catalyst concentration and reaction time were adjusted as above. Various changes were made.

9. Conducting research on the polymerization reaction of polyglycolic acid. laurylua stannous octoate When used in combination with alcohol, glycoside monomers are released after 2-4 hours. 96 cells were polymerized. This system can be used in six batch operations for the production of polylactic acid. Research it.

Catalytic initiators and chain control agents such as lauryl alcohol and water are It has the function of acting on the knit to open the ring. Thus, the activated nine reactants produce Polymerization reactions occur by sequential addition of new monomer units to the ends of long and medium chains. progresses. Each molecule of initiator has a chain of polymers, so the amount of monomer The relative concentration of diluted initiator determines the total molecular weight.

By changing this ratio, the molecular weight can be changed. Approximately 100.000 Polymers of glycolic acid with average molecular weights of It can be produced by using a weight group.

The viscosity of the Valley 1 combined sample was measured over a concentration range of t-10,5/0.05%, By extrapolating this value above the concentration to 0, calculate the intrinsic viscosity. The results of this experiment are It is shown in Table 1.

Intrinsic viscosity Intrinsic viscosity Molecular weight Polymer sample (CHCj3) (THF) (calculation (1) i: i COpO 17mθr (Lactic acid nigericolic acid) 0.2021 8.194” Polylactic acid (Batch 1) 0 ．． 287 - - Polylactic acid (batch 2) 0.489 0.195 26.00 0 Polymilk @ (Batch 3) -0,56595,000 Polylactic Acid (Batch 4) -0,22528,000 It is clear from the results listed in Table 1 that the reaction is true. It is preferable to carry out in the air, and the stannous octoate is also It is a highly active catalyst for crabs.

Polymers with low initial molecular weights can also be obtained with very long reaction times, i.e. That is, when the reaction time is long, scraps occur.

Using carbodiimide technology, Luteinizing Hormone Releasing Hormone (LHRH) It was conjugated to bovine gamma glopmin and extended onto the complex. bovine gamma glopmin LHRH ()・butene) 7.5■ν↓bi1 in 201ngk physiological saline 3mt -Ethyl-6-(6-dimethylaminoprobyl)-carbodiimide 150rn9 I reacted.

The pH of the solution was adjusted to 5.5 by adding 1N hydrochloric acid, and the reaction was allowed to rise at room temperature for 24 hours. It lasted for hours. After the reaction was completed, the reaction mixture was subjected to dialysis at 4°C with 6 changes of water. I went there for 48 hours. After dialysis, the complex is lyophilized and stored until the time of vaccine production. Stored at °C.

Properties of the complex Adding a hapten by adding a small amount of radioactive LHRH'i to a mixture containing the complex The total weight was calculated. The radioactivity of the complex was determined before and after the reaction. The addition rate of molecules is 95.1%, and the number of molecules added per 100,000 Daltons of protein molecules is 95.1%. The amount of butene was found to be 62 units. Formation of microcapsules using polylactic acid Research on microcapsule formation I did it. Poly D, L-lactic acid (batch 2, intrinsic viscosity, THF).

0.195 dlg-1; production batch 6, intrinsic viscosity, THF.

Solution of 0.565alg-1) (1.0g) in chloroform (100♂) (water-cooled solution) at 0°C. LHRH-live gamma-globulin complex (25 0ay) was added. Mechanically stir each resulting solution. Microsuspension of protein 9. Add ice-cold methanol (530 cr’) from the separatory funnel dropwise to Lactic acid was precipitated.

This suspension is left to settle, and the solvent is removed by tilting the tube. write The nuclided protein was resuspended in methanol, washed, and dried. drying The particles were then classified and tested for release properties. In the ninth stage of testing the release effect of nine microcapsules made from a series of polymers, the following was carried out. When following an accelerated elution method, luteinizing hormone-releasing hormone - bovine gamma - The release rate of the globulin complex was determined. Different molecular weights and particle sizes Four samples were tested. The results are shown in Table 2, and the measurement graph is shown in Figure 6. vinegar. In each sample, the classified particles (1001119) were placed in a T-nylon mesh bag. Fill this bag with 0.1M -NaCj-phosphate buffer (p) 17; Eto Pour 100 liters (liquid containing 20% H) and place in a bottle. This bottle has a screw Nine bottles with attached lids were mounted on a rotating shelf and kept at 67°C during the test period. A friend. Collect a portion of the sample every day for 8 days and change the soaking solution. in buffer The protein concentration was measured using a spectrofortometer (280 nm).

Table 2 -7 in 0.11,1-phosphate-NaCJ buffer (containing 20% EtoH). Measured after elution and sent to friend! J-D, LHRH- from L-lactic acid microcapsules Accelerated Release Rate of Gamma-Globulin Complex (Test Tube Test) Polymer (Batch) Sample granularity (indicated by number) Complex content p, 53-108 2 20 B 53-108 620 c 108-250 2 20 D 108-250 3 20 Elution period (days) Complex release rate (%) A long-acting veterinary implant according to the present invention is manufactured by the following method.

weight person 50% microparticles of LHRH-Bovine gamma-globulin protein complex Cholesterol 15% Etcel M-10015chi Enconzores 10chi Loop Retab 10chi PVP-90 (95% alcohol Medium solution; granulation aid) 10% (w/v) ÷ This LHRH-protein complex is It was made with a mixture of equal weights of materials A, B, C and D.

Mix each component of this composition together and granulate the resulting product. granular product was compressed to create a biodegradable implant in the form of a tablet. This locking operation is performed using a single punch. Moneschi F6 equipped with 0 This veterinary implant was made in two forms as shown in FIGS. 1 and 2. Bullet The round one (Fig. 1) is used to fire a short-range gas-powered pistol. It is. The insert type (Figure 2) is suitable for administration using an air-powered rifle. In the method, in combination with the outer shell part (outθr 5 hell) of a commercially available bullet (for example, when administering to animals in the field) Suitable for firing at relatively long distances).

The veterinary biodegradable implant made by the method of Example 2 was tested in the field in the following manner.

Field test 1 Australian Rusa deer (Cervus rusatimorθn51g) The heat season begins in July and lasts until the end of September. During this period, male Lusa deer consume food. The amount is substantially reduced, resulting in a worsening of the body's condition. 10 mature bucks All the LHRH-vaccine implants were administered 6 months before estrus. Single insert A veterinary implant in the form of a trocar was implanted subcutaneously with a trocar. Another herd of bucks (60 bucks) ) was the control group. The sexual behavior of this type of deer is suppressed and treated with this drug. All nine deer kept their weight constant during the estrus period, confirming the effectiveness of this treatment.

Field test 2 Deer leg development and subsequent antler growth are controlled by sex hormones (Buden ik, G, A,; 1985, Antler aevelopment in Cervidae eas, R,D.

Brown). 6 immature Chital deer (Axleaxis), 5 months old LHRH - Vaccine implant administered. Both treated and control animals The development of the legs was normal. However, regarding the growth of horns, the treatment of 6 animals A substantial reduction in growth was observed in all animals compared to control animals (Figure 4).

Field test 6 Sexual development and fertility in kangals and wallabies directly affect LHRH be done. In each case, a single veterinary implant is rifled into the animal's buttocks. It was devised to be injected into the body and administered subcutaneously. Good LHR for the following animals) The effect of I administration was observed.

(a) Red Kangal - (Macropua rufu8) Breeding of this animal is observed throughout the year, but is especially noticeable in spring/summer. The gestation period is approximately 66 days, and the child is They are grown in the bag for about 240 days. The above LHRH-vaccine implant was administered to three females. Administered to adult animals. In this case, no child will be born for 12 months.

In other words, this technology has the effect of suppressing reproduction.

LHRH administration was performed. Treated animals had no pups in their bags for 12 months. It was. The control animals have offspring, which are marsupials that breed during specific seasons and They reach their reproductive potential in January and give birth in late January.

The development of the cubs in the bag ends after 280 days. During the breeding season, male wallopies become more aggressive. This can be aggressive, resulting in large wounds.

(C-1) LHRH treatment on 6 adult female animals. 12 months There was no child in the bag.

Control animals had nine pups.

(c-2) Six mature male wallabies were subjected to the above treatment. sexual ability However, their behavior during the breeding season has changed (no longer aggressive). This effect is 12 I was recognized for several months. Although the outline and some specific examples of the present invention have been explained, the present invention deviates from the gist of the invention. may be implemented in various other ways and/or with various modifications. It should be understood that

1 to F Single dose vaccine E1 contraceptives Tatobe Mls Yo〆 Matrix: Water I H Raw 1 Go Fuhon F Old 2 Single fracture Waktef F-G-containing conversion type.

Ubejojo Kamisaigo Dato sound P hand skin i mostly, J: nmato 1 noshikumata: Kina 1 student 1 i book IG 3 Mouth minute 2. 108-250 mesh II mouth now 3. 53-1o8 0 ■ minutes 3. 108-250 Toshishe International Investigation Report lIIK---1=-='-1-=1--1+++, PCT/Al18770 0091US 4434153 US 4642233 US 4649043 US 4659558US 4450150 FR2287242us 43 51337G8 2103927 IN 156886EN [l OF ANN E.W.

Claims (17)

[Claims] 1. (a) a biodegradable polymeric material; (b) a plurality of biodegradable microcapsules embedded therein; and (c) an effective amount of a physiologically active ingredient encapsulated in said microcapsules; A long-acting implant characterized by containing. 2. Multiple biodegradable microcapsules have different decomposition rates. A biodegradable polymer material contains biodegradable microcapsules. The long-lasting effect according to claim 1, characterized by having a faster decomposition rate than Implant. 3. Multiple biodegradable microcapsules contain glycolic acid, lactic acid, their derivatives or is a relatively low molecular weight first polymer or copolymer derived from the mixture, and and molecular weight ratio derived from glycolic acid, lactic acid, derivatives thereof or mixtures thereof. Contains microcapsules made from relatively high secondary polymers or copolymers. The long-acting implant according to claim 2, characterized in that the long-acting implant is 4. Multiple biodegradable microcapsules are made of particles of two or more particle sizes. The long-acting implant according to claim 3, characterized in that: 5. Biodegradable polymeric materials are made from polyvinylpyrrolidone polymers or copolymers. The long-acting implant according to claim 4, characterized in that the long-acting implant is manufactured by 6. The biodegradable polymer material is bullet-shaped and is a polyvinylpyrrolidone-based polymer. The body or copolymer is sufficiently impact resistant to withstand the impact of the animal being treated. The long-acting plant according to claim 5, which has an impact strength. Ingredients. 7. Physiologically active ingredients are used in contraceptive vaccines, clostridial vaccines, and E. coli vaccines. vaccine, oral protein vaccine and allergy vaccine. 2. The sustained-release implant according to claim 1, characterized in that: 8. An effective amount of a sex hormone, a fragment thereof, or a derivative thereof, and an effective amount of a protein, veterinary avoidance containing hormone-protein complexes containing analogs or derivatives thereof. Claim 7, characterized in that a pregnancy vaccine is used as a vaccine component. A specific implant described in . 9. The sex hormone component in veterinary contraceptive vaccines is luteinizing hormone-releasing hormone. , luteinizing hormone, follicle maturation hormone, testosterone, estrogen and selected from its analogues, the protein component of which is tetanus toxoid proteins, bovine gamma globulin, serum albumin, and their analogues. The long-acting implant according to claim 8, characterized in that the long-acting implant is selected from agent. 10. Veterinary contraceptive vaccine releases tetanus toxoid protein and luteinizing hormone The long-acting plant according to claim 9, which is a complex with a hormone. Ingredients. 11. A veterinary contraceptive vaccine is one that is manufactured by: Tetanus toxoid protein with reduced cross-linking groups and multiple thiols in reduced state Prepare a peptide with a luteinizing hormone-releasing hormone or its analogue. A method consisting of combining these proteins and peptides to form a complex. Claim 10, characterized in that the product is manufactured by a method. Long-acting implant. 12. (a) a biodegradable polymeric material; (b) a plurality of biodegradable microcapsules embedded therein; and (c) an effective amount of a physiologically active ingredient encapsulated in said microcapsules; A method for manufacturing biodegradable microcapsules used in long-acting implants containing biodegradable polyamides derived from glycolic acid, lactic acid, their derivatives or mixtures. An ester or copolyester and a physiologically active ingredient are prepared and this physiologically active ingredient is prepared. Active ingredients are encapsulated in polyester or copolyester to form microcapsules. A manufacturing method characterized by forming. 13. The capsule forming process consists of preparing the polyester or copolyester in a suitable solvent. The polyester may be precipitated by mixing it with physiologically active ingredients at 13. The manufacturing method according to claim 12, characterized in that: 14. with a predetermined molecular weight used for the preparation of biodegradable microcapsules. A method for producing a biodegradable polyester or copolyester comprising: (a) One or more selected from glycolic acid, lactic acid, derivatives thereof and mixtures thereof (b) providing the above monomer and a predetermined amount of metal catalyst for its polymerization; Production characterized in that one or more monomers are polymerized at high temperature in the presence of said catalyst. Method. 15. One type selected from glycolic acid, lactic acid, derivatives and mixtures thereof The above monomers include cyclic diester, 1,4-dioxane-2,5-dione and selected from the group consisting of 3,6-dimethyl-1,4-thioxane-2,5-dione 15. The manufacturing method according to claim 14. 16. (a) a biodegradable polymeric material; (b) a plurality of biodegradable microcapsules embedded therein; and (c) an effective amount of veterinary active ingredient encapsulated in said microcapsules; The method of administering to animals (humans) one or more sustained-release implants containing (including treatment methods). 17. Veterinary active ingredients are used in contraceptive vaccines, clostridial vaccines, and E. coli vaccines. vaccination, oral protein vaccine, and allergy vaccine. 17. The method according to claim 16, wherein the method is cutin.